Pentoxifylline protects against endotoxin-induced acute renal failure in mice

Abstract

. Pentoxifylline protects against endotoxin-induced acute renal failure in mice. Am J Physiol Renal Physiol 291: F1090 -F1095, 2006; doi:10.1152/ajprenal.00517.2005.-Acute renal failure (ARF) in septic patients drastically increases the mortality to 50 -80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-␣ (TNF-␣), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-␣ and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-␣ and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 Ϯ 6.6 vs. 50.2 Ϯ 6.6 l/min, P Ͻ 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-␣ (1.00 Ϯ 0.55 vs. 7.02 Ϯ 2.40 pg/ml, P Ͻ 0.05) and serum IL-1␤ (31.3 Ϯ 3.6 vs. 53.3 Ϯ 5.9 pg/ml, P Ͻ 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 Ϯ 18.0 vs. 44.5 Ϯ 16.2 l/min, P Ͻ 0.05) and renal blood flow (0.86 Ϯ 0.08 vs. 0.59 Ϯ 0.05 ml/min, P Ͻ 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 Ϯ 5.8 vs. 178.0 Ϯ 7.6 mmHg ⅐ ml Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-␣, IL-1␤, and NO as well as a decrease in renal iNOS and ICAM-1. sepsis; tumor necrosis factor SEPSIS IS KNOWN TO OCCUR annually in 751,000 Americans and accounts for 215,000 deaths, a number equivalent to the overall deaths due to myocardial infarction (1). Moreover, sepsis is a major cause of acute renal failure (ARF) in intensive care units; sepsis-related ARF is associated with a 70 -80% mortality (33,34).Both inflammatory and vasoactive mediators are involved in the pathophysiology of sepsis-related ARF. TNF-␣ plays a central role in this process. Serum levels of TNF-␣ are induced early in endotoxemia in humans (25). Moreover, elevated serum levels of the type I and type II receptors for TNF-␣ are shown to be predictive factors for ARF in patients with septic shock (12). The role of TNF-␣ as a pathogenetic factor in experimental ARF was supported by the observation that pretreatment with a TNF-soluble receptor (TNF s R p55 ) significantly attenuated endotoxemia-related ARF (19). It has also been shown that endotoxemic ARF is caused by TNF acting directly on TNF receptor-1 in the kidney (6). TNF-␣ participates in the magnification of the response mediated by the release of other cytokines and active substan...

Combination Therapy with Albumin and Pentoxifylline Protects against Acute Kidney Injury during Endotoxemic Shock in Mice

“…In this endotoxemic shock model of AKI, pentoxifylline, contrary to previous results in the normotensive endotoxic model of AKI, [7] did not exhibit a protective effect on GFR. However, in the normotensive endotoxic model, pentoxifylline totally blocked the rise in TNF.…”

“…However, in the normotensive endotoxic model, pentoxifylline totally blocked the rise in TNF. [7] In contrast, in the present study, pentoxifylline had no detectable effects on the dramatic rise in TNF, which occurred in the endotoxemic shock model of AKI. Pentoxifylline is a phosphodiesterase inhibitor that increases cyclic AMP, a known vasodilator.…”

“…This occurred in the presence of plasma TNF concentrations that were many fold higher than those observed in the normotensive endotoxic AKI model. [7] These observations led to the tentative conclusion that this endotoxemic shock model of AKI was too severe to be attenuated by the proposed individual interventions alone. The possibility was therefore examined that the combination of albumin and pentoxifylline might exhibit a beneficial effect on AKI during endotoxemic shock.…”

“…[6] The phosphodiesterase inhibitor, pentoxifylline, has also been shown to block endotoxin-induced TNF production and protect against AKI. [7] It is unknown, however, whether any of these maneuvers is protective against AKI associated with septic shock. Moreover, to have clinical relevance, the intervention must be shown to be effective when administered after the endotoxic insult.…”

Hepatotoxicity; Preventive and Therapeutic Role of Dexamethasone in LPS/Endotoxin Induced.

“…Lowes and colleagues, Wei and associates in 2011, Rishi et al, all documented raised serum ALT and AST levels with hepatic architectural distortion in response to LPS administration. 15,19,20 Despite questionable role, research outcomes however exhibits beneficial results of corticosteroids in sepsis induced hepatotoxicity. Dexa- methasone was administered at a physiologically applicable dose of 3mg/kg (21) (2013) demonstrated that dexamethasone (given 1 hour before LPS) abolished LPS produced liver injury as proved by restoration of serum ALT and hepatic inflammation.…”